The challenge remains to reduce the incidence and mortality of oesophageal adenocarcinoma. No prevention or early detection strategy has yet been conclusively proven to reduce oesophageal adenocarcinoma or all cause mortality in individuals with Barrett’s oesophagus. Current approaches to oesophageal adenocarcinoma control are based largely on the symptomatic gastroesophageal reflux disease-Barrett’s oesophagus-oesophageal adenocarcinoma paradigm, but emerging data challenge many underlying assumptions (Figures and ).
The usefulness of endoscopic screening for Barrett’s oesophagus and oesophageal adenocarcinoma has come into question190
. In 2008, the American College of Gastroenterology Guidelines withdrew recommendations for endoscopic screening of patients with gastroesophageal reflux disease140
, and an American Gastroenterological Association Institute technical review concluded there was no direct evidence supporting endoscopic screening for either Barrett’s oesophagus or oesophageal adenocarcinoma in individuals with gastroesophageal reflux disease191
. An alternative research approach would be to develop a general population risk model taking advantage of existing data from consortia of observational and intervention studies as suggested previously for oesophageal adenocarcinoma ()192
. Such a model could be used to guide health policy and provide education on when to consult a medical provider (book in Other Information). Other measures derived from consortia data, such as H. pylori
status, anthropometric measures, and family history, could be used to develop a primary care risk model to facilitate risk stratification and guide referral (). Recent research has also identified promising leads for assessing biomarkers in the primary care setting, including blood tests95
and non-endoscopic oesophageal cytology193
, which could include biomarkers identifying persons with Barrett’s oesophagus who are at high risk for progression to oesophageal adenocarcinoma. High sensitivity and especially specificity of the primary care risk model, perhaps as afforded by such biomarkers, will be key in developing programs of prevention and early detection that have a significant impact on oesophageal adenocarcinoma incidence and mortality.
Prevention and control of oesophageal adenocarcinoma
There are data to support the effectiveness of endoscopic biopsy surveillance for early detection of oesophageal adenocarcinoma. Several retrospective studies have compared oesophageal adenocarcinomas arising in individuals who have been in a surveillance program for Barrett’s oesophagus to those with newly diagnosed oesophageal adenocarcinomas who had not been in endoscopic surveillance30,32,140,200-206
. Oesophageal adenocarcinomas were detected at earlier stages in the surveillance populations compared to those not in surveillance, and patients in surveillance generally, but not always, also had significantly improved survival. However, most of these studies had small sample sizes, some had short follow-up intervals and none were randomized control trials.
The leading chemoprevention candidate for oesophageal adenocarcinoma is currently aspirin, as protective associations have been reported consistently in population-based case-control and cohort studies as well as in meta-analyses130,132-134,196
. Inhibition of COX-2 has also been reported to decrease the incidence of oesophageal adenocarcinoma in an animal model of Barrett’s oesophagus207
. In Ireland, a population-based study of persons with reflux oesophagitis, Barrett’s oesophagus, oesophageal adenocarcinoma and population controls observed that use of aspirin and other non steroidal anti-inflammatory drugs (NSAIDs) was associated with a significantly reduced risk of Barrett’s oesophagus and oesophageal adenocarcinoma131
. Other population-based case-control studies have observed regular aspirin or other NSAID use to be associated with similar reductions in oesophageal adenocarcinoma incidence208,209
. A prospective cohort study of individuals with Barrett’s oesophagus reported that current users of aspirin and other NSAIDs had a reduced rate for progression to oesophageal adenocarcinoma compared with never users134
. Current users also had reduced progression to DNA content aneuploidy and tetraploidy compared with never users. Current use of aspirin and other NSAIDs has also been associated with a marked risk reduction in patients with multiple chromosome instability abnormalities at baseline with NSAID non-users having a 79% 10-year cumulative incidence of oesophageal adenocarcinoma compared to 30% for current NSAID users (p<0.001)130
. It should be noted that one small trial of the COX-2 inhibitor, celecoxib, evaluated changes in a number of surrogate endpoints after 48 weeks of treatment, initially reporting no difference in the proportion of biopsies with dysplasia, total surface area of Barrett’s oesophagus, prostaglandin levels, cyclooxygenase-1/2 mRNA levls or methylation of several tumor suppressor genes210
. However, a subsequent analysis using more detailed data available on a subset of the trial participants found a significant decrease in total Barrett’s area among those taking celecoxib211
. Taken together, these results suggest that the anti-inflammatory effects of aspirin and other NSAIDs may exert both early and late effects on neoplastic progression.
Proton pump inhibitors, a class of medications that substantially reduces gastric acid production, came into widespread use in the early to mid-1990s for treatment of symptoms of gastroesophageal reflux, among other indications. Several observational studies have examined the association between use of these drugs and surrogate endpoints for oesophageal adenocarcinoma, but with conflicting results. One recent retrospective cohort study examined pharmacy records to estimate use of proton pump inhibitors in 344 individuals without any dysplasia at initial endoscopy, reporting no association with the development of any dysplasia, but a statistically significant reduction in risk of high grade dysplasia and/or oesophageal adenocarcinoma212
. A potential limitation of the study, beyond the use of non-cancer endpoints, is the fact that more than 40% of the cohort were initially seen before proton pump inhibitors were generally available (1982-1992); thus any difference in risk of progression over time experienced by the cohort would bias the observed association with use of proton pump inhibitors. Another study examined the occurrence of regression of Barrett’s oesophagus among 188 persons taking proton pump inhibitors213
. They found no evidence of reduction in lenth of the Barrett’s segment after a mean of 5.1 years of treatment. As in vitro
studies suggest a possible antiproliferative effect of acid exposure in Barrett’s cell lines, mediated through p53, clinical trials are clearly needed to address the long-term effects of proton pump inhibitors on risk of oesophageal adenocarcinoma214
A randomized trial of aspirin and two doses of proton pump inhibitors for Barrett’s oesophagus without high-grade dysplasia is currently underway in the UK that includes all cause mortality outcome and may shed additional light on the effectiveness of aspirin and proton pump inhibitors as chemopreventive agents in persons with Barrett’s oesophagus without high-grade dysplasia215
. A randomized trial of high-risk individuals might also be considered in light of evidence that aspirin and other NSAIDs also act at an advanced stage of neoplastic progression130
. Additional candidate preventive measures, including weight loss, increased physical activity, smoking cessation, and increased intake of plant-based foods, may help reduce the incidence of oesophageal adenocarcinoma in the general population, and in high-risk persons defined by genetics, lifestyle or biomarkers. However, all remain to be demonstrated as effective in a prevention trial.
More aggressive approaches to prevention, including treating patients with Barrett’s oesophagus with photodynamic therapy (PDT) and radiofrequency ablation (RFA) have been evaluated in multicenter randomized trials with incomplete blinding and surrogate dysplasia primary endpoints148,149,198
. The PDT trial reported a decreased incidence of oesophageal adenocarcinoma as a secondary endpoint, with a non-significant increase in T2 and T3 oesophageal adenocarcinomas in the PDT arm, but patients who developed advanced cancers were excluded as treatment failures and oesophageal adenocarcinoma mortality may have been underestimated148,149
. Adverse events, such as photosensitivity, strictures, nausea/vomiting and pain, were also quite common (94%). The RFA trial had only surrogate primary and secondary endpoints, small sample size and short post-ablation follow up of only a few months in many patients. Although there was a decrease of borderline significance in the incidence of oesophageal adenocarcinoma among patients with high-grade dysplasia in the treatment arm during the short follow-up period (p=0.04), a trial with substantially larger sample size, longer follow up and primary endpoints of oesophageal adenocarcinoma incidence and mortality is needed to validate the effect. No patient with low-grade dysplasia developed oesophageal adenocarcinoma, consistent with the known low risk, transient nature and lack of robust reproducibility of this diagnosis (Box 2
). In addition, approximately 10% of patients receiving RFA for non-nodular dysplasia had adverse events requiring additional medical care including upper gastrointestinal bleeding, chest pain requiring hospitalization, and strictures requiring dilation, compared to none in the control arm. Endoscopic mucosal resection (EMR) is frequently performed in the setting of nodular dysplasia for effective selection of patients for endoscopic therapy prior to RFA, and the combination of EMR and RFA can result in a constellation of adverse events affecting more than 20% of patients, including bleeding, oesophageal laceration, oesophageal perforation, oesophageal stricture requiring dilatation, fever and chest pain requiring hospitalization216
. Although the length of follow up in the RFA trial was insufficient to assess recurrence of Barrett’s oesophagus after therapy, the neosquamous epithelium after ablation is prone to undergo the fate of its precursor, the native oesophageal squamous epithelium, which lacks the mucosal defences of specialized intestinal metaplasia () and recurrence of Barrett’s oesophagus has been reported in up to two-thirds of patients217
Conclusions and perspective
The incidence of oesophageal adenocarcinoma has risen more rapidly than any other cancer in Western countries, and there is evidence for increasing incidence in regions of Asia where the diagnosis was previously almost unknown. Current approaches for controlling oesophageal adenocarcinoma incidence and mortality largely based on endoscopic investigation of symptomatic gastroesophageal reflux disease and histology-guided surveillance and treatment of persons with Barrett’s oesophagus have significant limitations (, Box 2
). New oesophageal adenocarcinoma prevention strategies will be needed to overcome these limitations and decrease the current high mortality associated with oesophageal adenocarcinoma ().
Advances have been made over the past decade in our understanding of host and environmental factors associated with oesophageal adenocarcinoma, including the role of obesity as well as the protective associations of aspirin and other NSAIDs. These and other factors can guide development of population risk models192
. Advances have also been made that can assist development of primary care risk models, including family history, H. pylori
testing, non-endoscopic cytology, and blood tests. With rapid advances in DNA array technology, more precise and higher resolution measurements of both the constitutive genome and the evolving neoplastic genome are now possible with platforms that can be translated into the clinic setting. However, the complexity of the process of neoplastic progression suggests that no single measure will likely be sufficient for practical clinical oesophageal adenocarcinoma risk stratification over a person’s lifetime (Box 3
A significant remaining challenge is that no intervention, including lifestyle modification, chemoprevention, or medical or surgical treatments, has yet been convincingly shown to reduce oesophageal adenocarcinoma incidence and/or mortality. Consortia with multidisciplinary expertise in population, genomic, computational, clinical and other sciences will be required to effectively address these challenges with the goals of developing personal risk stratification based on interactions among environmental factors, the constitutive genome and the evolving neoplastic genome and delivering personalized care in the form of interventions tailored to an individual’s oesophageal adenocarcinoma risk.
At a glance
The paradigm that Barrett’s oesophagus develops as a consequence of symptomatic gastroesophageal reflux disease and predisposes to oesophageal adenocarcinoma has dominated clinical thought for more than three decades. However, current approaches for controlling the incidence and mortality of oesophageal adenocarcinoma largely based on endoscopic investigation of individuals with symptomatic gastroesophageal reflux disease, and histology-guided surveillance and treatment of individuals with Barrett’s oesophagus have significant limitations.
Barrett’s oesophagus rarely progresses to oesophageal adenocarcinoma, and a theory has recently been proposed that mucosal defences in most patients with Barrett’s oesophagus represent successful adaptations to the harsh intra-oesophageal environment of chronic gastroesophageal reflux disease. Several mucosal defences that arise in Barrett’s oesophagus have been identified, including secretion of bicarbonate and mucous, expression of claudin-18 tight junctions, overexpression of defence and repair genes, and resistance to prolonged and repeated acid exposure.
The incidence of oesophageal adenocarcinoma has been rising at an alarming rate in the US, Western Europe, Australia, and in other developed countries over the past four decades, and there is disquieting evidence of increased incidence of oesophageal adenocarcinoma in some Asian populations.
Four risk factors, gastroesophageal reflux disease, obesity, cigarette smoking and poor diet, account for the majority of oesophageal adenocarcinomas. Obesity may act at early and late stages of progression and interact biologically with gastroesophageal reflux disease, although a substantial proportion of the effect of obesity is likely to be through other pathways.
Neoplastic progression to oesophageal adenocarcinoma is characterized by genomic instability, including chromosome instability in most cases, disruption of regulatory pathways and temporal evolution of clones that may be modulated by host and environmental risk and protective factors. Proper measurement and quantification of the complexity of these alterations creates opportunities and challenges for improved risk stratification, prevention and early detection.
Aspirin and other non steroidal anti-inflammatory drugs have been consistently reported to have a protective association with oesophageal adenocarcinoma in case-control and cohort studies as well as meta-analyses; they may be useful in patients at both early and late stages of progression.
No intervention, whether based on lifestyle modification, chemoprevention, or medical or surgical treatments, has yet been convincingly demonstrated in a randomized trial to reduce incidence and/or mortality of oesophageal adenocarcinoma; this remains a particularly crucial area of unmet research need. New oesophageal adenocarcinoma prevention strategies are proposed to overcome these limitations.